The purpose of this study is to determine if therapeutic plasma exchange (TPE) can reduce cell surface proteins circulating in plasma, including soluble receptors and extracellular vesicles (EVs).
Background:
Proteins expressed on the tumor surface are the focus of many targeted therapies, including antibody-based treatments, antibody-drug conjugates (ADCs), T cell receptor (TCR) fusion constructs, and chimeric antigen receptor T-cell (CAR-T) products. These target proteins can be shed from the tumor surface into the plasma as a soluble receptor or an EV, which may prevent targeted treatments from reaching the tumor. High levels of soluble MSLN (sMSLN) is associated with poor clinical outcomes in mesothelioma. Additionally, sMSLN and EV-positive (EV+) MSLN can interfere with MSLN targeted immunotoxins, ADCs, and CAR-T. Similar findings are seen with elevated levels of soluble PDL1, BCMA, and LAG3.
We recently reported that TPE decreases soluble PD-L1 (sPDL1) and PDL1-positive EVs. TPE is a routine procedure indicated in several medical conditions, including certain autoimmune disease and hyperviscosity syndromes, where the patient’s blood is removed, the plasma is separated out, then this plasma is exchanged with replacement fluid to give back to the patient. The procedure reliably removes proteins in the plasma that are larger than albumin (65-70 kDa), but is known to remove smaller substances as well. These results have culminated in a clinical trial to understand if using TPE to decrease circulating PD-L1 can restore anti-cancer immunity in patients with metastatic melanoma treated with immune checkpoint inhibitors (ICIs). Based on these findings, we hypothesized that TPE could similarly reduce sMSLN. We used 16 patient samples from the sPDL1 project in a feasibility study to determine if TPE could reduce sMSLN [6]. Our results show that TPE does reduce sMSLN (p < />
Our sPDL1 and sMSLN results suggest that TPE can reduce these circulating proteins, which contribute to targeted therapy resistance. These findings may apply to other cell surface proteins as well. Our study aims to address a critical gap in our understanding of the soluble receptors and EVs present in the plasma, and whether TPE can significantly reduce these circulating proteins.
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